Transdermal and Topical Delivery Systems - Product Development and Quality Considerations

Home , Absorption (skin), Drug delivery, Transdermal

Guidance for Industry

DRAFT GUIDANCE

This guidance document is being distributed for comment purposes only.

Comments and suggestions regarding this draft document should be submitted within 90 days of publication in the Federal Register of the notice announcing the availability of the draft guidance. Submit electronic comments to https://www.regulations.gov. Submit written comments to the Dockets Management Staff (HFA-305), Food and Drug Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852. All comments should be identified with the docket number listed in the notice of availability that publishes in the Federal Register.

For questions regarding this draft document, contact (CDER) Mohamed Ghorab 240-402-8940.

U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER)

November 2019 Pharmaceutical Quality/CMC

14981899 Dft

Transdermal and Topical Delivery Systems - Product Development and Quality Considerations

Guidance for Industry

Additional copies are available from: Office of Communications, Division of Drug Information Center for Drug Evaluation and Research Food and Drug Administration 10001 New Hampshire Ave., Hillandale Bldg., 4th Floor Silver Spring, MD 20993-0002 Phone: 855-543-3784 or 301-796-3400; Fax: 301-431-6353 Email: [email protected] https://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm

U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER)

November 2019 Pharmaceutical Quality/CMC

Contains Nonbinding Recommendations Draft — Not for Implementation TABLE OF CONTENTS

I. INTRODUCTION...... 1 II. BACKGROUND ...... 1 A. General ...... 1 B. Regulatory Status ...... 3 III. TDS PRODUCT DEVELOPMENT ...... 4 A. Quality Target Product Profile ...... 4 B. Critical Quality Attributes ...... 5 1. TDS Product ...... 5 2. Drug Substance ...... 5 3. Excipients and Components ...... 6 4.Identifying Labeling ...... 7 C. Product and Process Development ...... 7 IV. INFORMATION TO BE SUBMITTED IN AN APPLICATION ...... 8 A. Pharmaceutical Development ...... 8 1. Batch Formula ...... 10 2. Expectations for Registration/Exhibit Batches ...... 10 3. Product Characterization Studies ...... 11 4. Proposed Manufacturing Changes ...... 16 B. Manufacture ...... 17 C. Control of TDS Product ...... 19 D. Additional Stability Studies ...... 24 V. SPECIAL TOPICS ...... 24 A. Product Adhesion Considerations ...... 24 B. Product Storage and Disposal – Labeling Considerations ...... 25

Contains Nonbinding Recommendations Draft — Not for Implementation 1 Transdermal and Topical Delivery Systems - Product Development 2 and Quality Considerations 3 Guidance for Industry1 4 5 6 This draft guidance, when finalized, will represent the current thinking of the Food and Drug 7 Administration (FDA or Agency) on this topic. It does not establish any rights for any person and is not 8 binding on FDA or the public. You can use an alternative approach if it satisfies the requirements of the 9 applicable statutes and regulations. To discuss an alternative approach, contact the FDA staff responsible 10 for this guidance as listed on the title page. 11 12 13 14 I. INTRODUCTION 15 16 This guidance provides recommendations to applicants and manufacturers of transdermal and 17 topical delivery systems (TDS)2 regarding the pharmaceutical development and quality 18 information to include in new drug applications (NDAs) and abbreviated new drug applications 19 (ANDAs).3,4 Specifically, the guidance discusses FDA’s current thinking on product design and 20 pharmaceutical development, manufacturing process and control, and finished product control. It 21 also addresses special considerations for areas where quality is closely tied to product 22 performance and potential safety issues, such as adhesion failure and the impact of applied heat 23 on drug delivery. 24 25 In general, FDA’s guidance documents do not establish legally enforceable responsibilities. 26 Instead, guidances describe the Agency’s current thinking on a topic and should be viewed only 27 as recommendations, unless specific regulatory or statutory requirements are cited. The use of 28 the word should in Agency guidances means that something is suggested or recommended, but 29 not required. 30 31 II. BACKGROUND 32 33 A. General 34

1 This guidance has been prepared by the Office of Pharmaceutical Quality and Office of Generic Drugs in the Center for Drug Evaluation and Research, in consultation with the Center for Devices and Radiological Health, and the Office of Combination Products, at the Food and Drug Administration. 2 For the purpose of this guidance, both transdermal and topical delivery systems are referred to by the acronym “TDS.” 3 Some TDS (such as microneedles, active transport TDS, reservoir TDS, and TDS applied to broken skin) have other considerations that are not addressed in this guidance. 4 The general principles in this guidance can also be applied to nonapplication drug products; for example, over-the- counter drugs products marketed under the monograph regulatory construct (see 21 CFR part 330).

1 Contains Nonbinding Recommendations Draft — Not for Implementation 35 Transdermal delivery systems are designed to deliver an active ingredient (drug substance) 36 across the skin and into systemic circulation, while topical delivery systems are designed to 37 deliver the active ingredient to local tissue.5 Both delivery systems present similar manufacturing 38 and quality control concerns and similar risks to patients. TDS can be broadly divided into 39 matrix type and liquid or gel reservoir type delivery systems. 40 41 Matrix type TDS contain one or more active ingredients dissolved or partially suspended in a 42 mixture of various components, including adhesives, penetration enhancers, softeners, and 43 preservatives, and are typically manufactured using solvent, hydrogel, or hot melt-based 44 practices. An example of a matrix type TDS is shown in Figure 1, but matrix TDS may include 45 additional layers and/or more complex designs. 46 47 Figure 1. Matrix Type Transdermal or Topical Delivery System 48 49

50 51 Reservoir type TDS similarly contain a variety of components in liquid or semi-solid form; 52 however, reservoir type TDS utilize a heat-sealed area to entrap the active gel between the 53 backing membrane and a microporous membrane. An example of a reservoir type TDS is shown 54 in Figure 2. Because of the inherent failure modes and safety risks associated with the reservoir 55 TDS, FDA recommends TDS manufacturers and applicants focus development efforts on matrix 56 type TDS.6 57

5 Topically administered liquid and semi-solid drug products without a carrier device (e.g., gels, creams, lotions, foams, ointments, or sprays) are not considered to be TDS and are not covered by this guidance, even though they can be formulated to provide local, or in some cases, transdermal delivery of the drug. 6 Applicants are strongly encouraged to consult the Office of Pharmaceutical Quality early in the development process prior to pursuing a reservoir design.

2 Contains Nonbinding Recommendations Draft — Not for Implementation 58 Figure 2. Reservoir Type Transdermal or Topical Delivery System

59 60 61 B. Regulatory Status 62 63 Transdermal and topical delivery systems are combination products as defined by 21 CFR part 3, 64 and must comply with 21 CFR part 4 subpart A (Current Good Manufacturing Practice 65 Requirements for Combination Products). Within 21 CFR part 4, there is description of how 66 requirements from 21 CFR parts 210 and 211 (drug CGMPs) and 21 CFR part 820 (device 67 Quality System regulation) apply to combination products.7 68 69 In particular, design controls (21 CFR part 820.30) apply to drug-device combination products 70 including TDS.8 Essentially, design control activities should confirm that there are no negative 71 interactions between constituent parts and assure that their combined use results in a combination 72 product that is safe and effective and performs as expected. Guidance for industry on 73 pharmaceutical development also addresses product design and development procedures,

7 For related guidance, see FDA guidance for industry and staff Current Good Manufacturing Practice Requirements for Combination Products (January 2017). We update guidances periodically. For the most recent version of a guidance, check the FDA guidance web page at https://www.fda.gov/RegulatoryInformation/Guidances/default.htm.8 As can be the case for components of other single-entity combination products, some components of TDS may be treated as components of both the drug and device constituent parts of the combination product. Because the purpose of this guidance is to offer technical recommendations relating to product development and assessment, we use the general term “component(s)” throughout the guidance to avoid unnecessary complexity regarding such incidental regulatory issues.9 See FDA guidance for industry Q8(R2) Pharmaceutical Development (November 2009). We reference International Conference for Harmonisation (ICH) guidelines, which address complex scientific issues or set forth first interpretations of regulatory requirements, and correspond to FDA draft and final guidance documents, respectively. 8 As can be the case for components of other single-entity combination products, some components of TDS may be treated as components of both the drug and device constituent parts of the combination product. Because the purpose of this guidance is to offer technical recommendations relating to product development and assessment, we use the general term “component(s)” throughout the guidance to avoid unnecessary complexity regarding such incidental regulatory issues.9 See FDA guidance for industry Q8(R2) Pharmaceutical Development (November 2009). We reference International Conference for Harmonisation (ICH) guidelines, which address complex scientific issues or set forth first interpretations of regulatory requirements, and correspond to FDA draft and final guidance documents, respectively.

3 Contains Nonbinding Recommendations Draft — Not for Implementation 74 reflecting quality by design principles.9 While quality by design and design controls share 75 similar characteristics and goals, the device Quality System regulation (21 CFR part 820) 76 includes specific requirements for design development that manufacturers must satisfy.10 77 78 It may be possible to leverage many aspects of pharmaceutical development as described in 79 International Conference for Harmonisation ICH Q8(R2)11 to achieve compliance with design 80 controls. For example, the Quality Target Product Profile (QTPP) (see section III.A. below) is 81 similar to “design inputs” (21 CFR part 820.30(c)), which ensure that design requirements are 82 appropriate to address the intended use of the product. Further, studies conducted to verify that 83 the critical quality attributes (CQAs) are met in the finished product may also address 84 requirements for design “verification” and “validation” (21 CFR part 820.30(f), (g)), which 85 ensure that the product’s “design outputs” (21 CFR part 820.30(d)) result in a product that safely 86 and effectively achieves its intended effects).12 87 88 III. TDS PRODUCT DEVELOPMENT 89 90 The following section provides an overview of considerations for product and process 91 development, described from a pharmaceutical development perspective. As described above, 92 development of a TDS product must also be compliant with design controls (21 CFR part 93 820.30). We recognize that the terminology used in 21 CFR part 820.30 can differ from that used 94 in a particular pharmaceutical development program. Where pharmaceutical development 95 practices are leveraged and built upon to demonstrate compliance with design controls for a TDS 96 product, applicants should be able to communicate to FDA how the terminology they use relates 97 to design control principles and requirements. 98 99 A. Quality Target Product Profile 100 101 Prior to TDS development, the applicant should establish the desired quality target product 102 profile (QTPP). The QTPP is a prospective summary of the quality characteristics of the TDS 103 product that ideally will be achieved to ensure the desired quality, taking into account safety and 104 efficacy of the product (ICH Q8(R2)). In general, QTPP elements and their quality 105 considerations for TDS may include: 106

9 See FDA guidance for industry Q8(R2) Pharmaceutical Development (November 2009). We reference International Conference for Harmonisation (ICH) guidelines, which address complex scientific issues or set forth first interpretations of regulatory requirements, and correspond to FDA draft and final guidance documents, respectively. 10 For example, requirements under 21 CFR part 820 for design control, purchasing controls, management responsibility and corrective and preventive action must be met. See FDA guidance for industry Current Good Manufacturing Requirements for Combination Products (January 2017) for additional information regarding options for complying with the requirements of 21 CFR part 820 for a combination product. 11 See footnote 9. 12 Additional requirements for design control include preparation of a design plan (21 CFR part 820.30(b)) and holding review meetings with specified personnel in attendance (21 CFR part 820.30(e)). See Current Good Manufacturing Requirements for Combination Products for additional information regarding design control requirements for combination products and other CGMP requirements for combination products that include a device constituent part.

4 Contains Nonbinding Recommendations Draft — Not for Implementation QTPP Element Quality Considerations In vivo delivery of active ingredient to Formulation design and manufacturing achieve therapeutic effect control Minimization of residual drug Formulation design Adherence for duration of wear period Excipient selection, component control, physical design (shape, dimensions, etc.), and manufacturing control Minimization of irritation Formulation design Chemical and physical stability for Formulation design, container closure shelf life attributes, storage conditions Non-drug substance-related impurities Excipient selection and manufacturing control 107 108 Other QTPP elements may exist depending on therapeutic need, patient population, or other 109 functional property requirements. For example, the size of the finished product may be a QTPP 110 element depending on the location on the body where the product is to be applied or if the patient 111 population is pediatric. 112 113 B. Critical Quality Attributes 114 115 1. TDS Product 116 117 Early in the TDS development process, the applicant should generate a list of potential CQAs. A 118 CQA is a physical, chemical, biological, or microbiological property or characteristic that should 119 be within an appropriate limit, range, or distribution to ensure the desired product quality (ICH 120 Q8(R2)). Knowledge of the QTPP for the product, in combination with prior knowledge, risk 121 assessments, and/or experimentation, can be used to develop the list of product CQAs. Each 122 CQA, either alone or in concert with one or more other CQAs, should relate to one or more 123 elements of the TDS product QTPP. The list of product CQAs can be modified as product 124 development progresses and new knowledge is gained. The CQAs of the drug substance(s), 125 excipients, components and container closure system should also be identified in the application. 126 127 For TDS, CQAs typically include appearance (such as lack of visible crystals), dimensions, 128 uniformity of dosage units, assay, permeation enhancer content, impurities and degradants, in 129 vitro drug release profile, preservative/antioxidant content (if present), peel adhesion, tack, 130 release liner peel strength, shear strength, cold flow, residual solvents, residual monomers, 131 microbial limits, and package integrity. 132 133 2. Drug Substance 134 135 Selection of a drug substance should be justified based on the physicochemical and biological 136 properties of the drug substance that can influence the performance of the TDS product and its 137 manufacturability. In particular, properties that influence the rate of delivery, such as molecular 138 weight, melting point, partition coefficient, pKa, aqueous solubility, and pH, should be 139 considered. Other characteristics of the drug substance such as particle size, crystal form, and 140 polymorphism should be evaluated and justified in terms of product performance.

5 Contains Nonbinding Recommendations Draft — Not for Implementation 141 142 3. Excipients and Components 143 144 Excipients and components used in TDS can include various adhesives, permeation enhancers, 145 rate controlling or non-rate controlling membranes, solubilizers, plasticizers/softeners, or 146 tackifiers, all of which can influence the quality and performance attributes of TDS. 147 148 Rigorous qualification of key excipients and components is important to ensure optimum product 149 quality attributes in transdermal and topical formulations, and facilitates the postapproval change 150 process for changes in the raw materials, manufacturing process, or suppliers. 151 152 For example, when qualifying the adhesives in a TDS product, an applicant should consider the 153 following attributes: 154 155 • For adhesive polymer(s) as raw material(s): molecular weight, polydispersity, 156 spectroscopic analysis (e.g., infrared radiation (IR) absorption), thermal analysis, intrinsic 157 or complex viscosity, and measurement of residual monomers, dimers, solvents, heavy 158 metals, catalysts, and initiators. 159 160 • For adhesive as a laminate (in the absence of the active ingredient and other excipients): 161 residual solvents, peel, tack, shear, and adhesion. 162 163 • For adhesive in the final product (along with drug substance and other excipients and 164 components): identification, residual monomers, dimers, and solvents; impurities; loss on 165 drying; and uniformity. Other properties to be considered include the viscoelastic 166 properties (such as elastic modulus (G’), viscous modulus (G”), and creep compliance 167 (J)), and functional properties including, but not limited to, peel, shear, adhesion, tack, in 168 vitro drug release, and in vitro drug permeation. 169 170 The properties of an adhesive as raw material (e.g., rheology, including intrinsic viscosity and 171 complex viscosity) can impact the final product quality attributes. Adhesive suppliers’ 172 specifications are often wide; thus, adhesive raw material received throughout the life cycle of 173 the product may vary greatly within the adhesive suppliers’ specifications. For example, the 174 rheological properties of the adhesive lots used in the pivotal in vivo trial for TDS (e.g., 175 bioequivalence (BE), Pharmacokinetic (PK), adhesion studies) may not be consistent with the 176 supplier’s previously manufactured adhesive lots or their future adhesive lots. Therefore, 177 applicants should request historical rheology values from the adhesive manufacturer to better 178 understand their process capabilities and the potential influence of variability in the adhesive

6 Contains Nonbinding Recommendations Draft — Not for Implementation 179 rheology on the final product. This can further assist applicants in assessing the need to establish 180 or tighten internal controls for the raw material. 181 182 Identifying, evaluating, and properly controlling similar quality attributes of other key 183 components of TDS products will enhance product and process understanding of the TDS 184 throughout its life cycle. 185 186 4. Identifying Labeling 187 188 Applicants are encouraged to incorporate a representative label early in development to assure 189 the labeling process or inks utilized for printing do not interact with the TDS product, and to 190 properly assess inks during extractable and leachable studies. The identifying label is typically 191 placed on the backing membrane of TDS and should, at minimum, include the product name and 192 strength. 193 194 Transdermal and topical systems that are clear, translucent, or colored to match human skin tones 195 can make it difficult to find the TDS on the patient, and have led to medication administration 196 errors when patients or caregivers fail to remove old systems and apply more than one system at 197 a time. Clear or translucent TDS may also be difficult to find if they detach prematurely from a 198 patient, thereby increasing the potential for secondary or accidental exposure of the drug to a 199 health care provider, caregiver, or child. Therefore, we recommend the backing membrane be 200 printed with ink that has adequate contrast and remains visible for the duration of system wear 201 and after disposal. 202 203 C. Product and Process Development 204 205 The principles of quality by design (QbD) and elements of pharmaceutical development 206 discussed in ICH Q8(R2), Q9, and Q1013 should be applied throughout the TDS life cycle to 207 ensure TDS products have the identity and strength, and meet the quality and purity 208 characteristics required under section 501(a)(2)(B) of the Federal Food, Drug, and Cosmetic Act 209 (FD&C Act). 210 211 TDS can be as simple as a single drug substance dissolved in a single adhesive, or highly 212 complex, multi-component, multi-adhesive, multi-laminate matrices. Excipients and components 213 in TDS can include various adhesive systems, permeation enhancers, rate controlling or non-rate 214 controlling membranes, solubilizers, plasticizers/softeners, or tackifiers. 215 216 As a general principle, product development strategies should seek to minimize product 217 complexity while still achieving the QTPP. Less complex products are likely to have fewer 218 potential failure modes than more complex products. Product and process controls can be 219 simplified as product complexity decreases, which can reduce the risk of manufacturing 220 problems occurring during routine commercial manufacture. 221

13 See FDA guidances for industry Q8(R2) Pharmaceutical Development (November 2009), Q9 Quality Risk Management (June 2006), and Q10 Pharmaceutical Quality System (April 2009).

7 Contains Nonbinding Recommendations Draft — Not for Implementation 222 Systematic quality risk assessments and process characterizations can support the identification 223 of appropriate controls for manufacturing process variables, in order to produce TDS products 224 with acceptable CQAs. Risk assessments can also help define the robustness of certain critical 225 material attributes (CMAs) and critical process parameters (CPPs), such as raw material 226 characteristics, hold times and equilibration periods. 227 228 IV. INFORMATION TO BE SUBMITTED IN AN APPLICATION 229 230 An applicant must provide technical data and information in sufficient detail to permit the 231 Agency to make a knowledgeable judgment about whether to approve the application or whether 232 grounds exist under section 505(d)14 or 505(j)15 of the FD&C Act to refuse to approve the 233 application. This includes information about the drug substance16 and information about the TDS 234 product.17 235 236 The following sections provide recommendations to applicants about pharmaceutical 237 development and quality information to be included in the application sections described in ICH 238 M4Q.18 239 240 A. Pharmaceutical Development 241 242 As described in ICH M4Q, section 3.2.P.2 of the application should contain information on 243 studies conducted to establish that the dosage form, formulation, manufacturing process, 244 container closure system, microbiological attributes, and usage instructions specified in the 245 application are appropriate for the intended use of the TDS product. The applicant should 246 address the following: 247 248 • A description of the QTPP. 249 250 • A list of the CQAs of the TDS product, along with the limit, range, or distribution 251 associated with each CQA and appropriate justification. 252 253 • Identification of those aspects of the drug substance, excipients, container closure system, 254 and manufacturing processes important to attaining product quality. 255 256 o In particular, the selection of excipients and components, their concentrations (as 257 appropriate), and their functional characteristics affecting TDS performance 258 should be discussed. For example, the applicant should describe the impact of 259 penetration enhancers on the adhesive properties of the TDS, solubility of the 260 drug substance in the blend, and skin permeation.

14 See 21 CFR part 314.50(d). 15 See 21 CFR part 314.94(a)(9). 16 See 21 CFR parts 314.50(d)(1)(i) and 314.94(a)(9). 17 See 21 CFR parts 314.50(d)(1)(ii) and 314.94(a)(9). Please note information about the combination product as a whole (referred to as TDS product in this guidance) should be provided in those eCTD sections intended for the drug product alone. 18 See FDA guidance for industry M4Q: CTD — Quality (August 2001).

8 Contains Nonbinding Recommendations Draft — Not for Implementation 261 262 o Applicants should specify the allowable ranges around the process parameters and 263 material attributes that have a potential to impact TDS product CQAs with 264 justification and describe how they will be monitored. 265 266 • A description of the quality risk assessments, potential failure modes, and product and 267 process control strategies. 268

9 Contains Nonbinding Recommendations Draft — Not for Implementation 269 270 1. Batch Formula 271 272 For processes that use solvated raw materials, batch formulas should be designed to tolerate 273 variation in the solvent content of raw materials. Drug substance overages and excipient excesses 274 can be added to a batch to account for evaporation during drying, but the amount of overage or 275 excess should be controlled and justified by process development studies. Applicants should 276 describe any cross-linking reactions since these reactions impact the chemical composition and 277 quality of the finished product. 278 279 2. Expectations for Registration/Exhibit Batches 280 281 Applicants should submit data for registration/exhibit batches manufactured from three distinct 282 laminates, where each laminate is made using different lots of drug substance, adhesives, 283 backing, and/or other critical elements in the TDS product. Release and stability sampling should 284 be representative of the full length and width of the laminates to demonstrate that the 285 manufacturing process is robust. 286 287 Any clinical batch (e.g., those used in phase 3, PK, BE, adhesion, or irritation and sensitization 288 studies) should be included in the formal stability program.19,20 Applicants should provide the 289 executed batch records and certificates of analysis for all batches used in clinical and BE studies, 290 including placebo batches. Placebo batches should include all inactive ingredients and 291 components and representative printing. 292 293 Applicants should report the actual yields, theoretical yield, and percentages of theoretical yield 294 from the conclusion of each appropriate phase of manufacturing, processing, packaging, and 295 holding. The theoretical yield should be calculated for each batch prospectively. For example, if 296 a coating process is stopped due to a manufacturing issue, the theoretical yield should be based 297 on the mass that was intended to be coated rather than the mass that was actually coated. The 298 yield for TDS processes may be lower than the usual yield for many other drug manufacturing 299 processes. However, abnormally low yields in the TDS submission batches should be explained 300 in the application. 301 302 Because of the sensitivity of TDS products to small differences in manufacturing process, a 303 master table comparing the clinical, BE, registration/exhibit, and proposed commercial batches 304 should be included in section 3.2.P.2.3 of the application. For each batch, this table should 305 specify the manufacturing process used (including equipment, and manufacturing scale, and 306 those parameters that could directly or indirectly impact a CQA), and the results of critical in- 307 process tests (specifying the test procedure and acceptance criteria), yield, and reconciliation 308 data. The table should also include links to any information referenced from other parts of the 309 submission. It should also clarify whether these batches were packaged to completion at the die 310 cutting and pouching stage. 311

19 See FDA guidance for industry Q1A(R2) Stability Testing of New Drug Substances and Products. 20 See FDA guidance for industry ANDAs: Stability Testing of Drug Substances and Products: Questions and Answers (May 2014).

10 Contains Nonbinding Recommendations Draft — Not for Implementation 312 3. Product Characterization Studies 313 314 Because of the uniqueness of the TDS dosage form, specialized developmental studies and 315 evaluations are recommended to demonstrate full product understanding in both new and 316 abbreviated new drug applications. Several such studies/evaluations are discussed below. 317 318 a. Skin Permeability 319 320 Skin permeability is a function of permeant thermodynamic activity and degree of saturation of 321 the drug substance in the TDS. The solubility and degree of saturation of the drug substance in 322 the TDS should be evaluated, and their impact on the performance of the TDS understood. 323 324 b. Crystallization 325 326 Generally, crystallization of the drug substance in the TDS product should be avoided. If 327 crystallization occurs, studies should be conducted to assess its impact on the in vivo 328 performance and adhesion of TDS. 329 330 c. Thermodynamic Stability of Drug Substance 331 332 To confirm thermodynamic stability of the drug substance, the risk of precipitation or salt 333 formation during manufacturing and storage should be evaluated. If there is an equilibrium 334 between different salt forms, the kinetics to reach this equilibrium should be thoroughly 335 characterized. The impact of this equilibrium on TDS performance should be evaluated with 336 relevant in vitro drug release, permeation, and/or clinical data. 337 338 d. Strength 339 340 The strength of a transdermal system should be expressed as a rate (e.g., XX mg/day), whereas 341 the strength of a topical system should be expressed as a percent total drug load. For transdermal 342 systems, the strength can be derived from and supported by either PK data or by residual drug 343 analysis performed on used transdermal systems. The first approach involves the derivation of a 344 clearance (Cl) value from absolute bioavailability of the drug and multiplying that by the 345 concentration (Css) at the steady state. The second approach involves the measurement of the 346 amount of drug left in the transdermal systems at the end of the wear period and dividing the 347 “consumed amount” by the wear period. 348 349 Although the strength of a topical system is expressed as percent total drug load, a residual drug 350 analysis should still be conducted. 351 352 e. Residual Drug 353 354 Consistent with FDA guidance for industry Residual Drug in Transdermal and Related Drug 355 Delivery Systems (August 2011), scientific justification sufficient to support the amount of 356 residual drug in a TDS should be included in the pharmaceutical development section of the 357 application. To provide a robust analysis of the residual drug, we recommend the following:

11 Contains Nonbinding Recommendations Draft — Not for Implementation 358 359 1. Data should be based on analysis of the used TDS and not on a theoretical 360 calculation. 361 2. The amount of drug left on the skin surface should be assessed. Any drug that may 362 have been transferred to packaging or other components of the TDS during storage or 363 use should be accounted for in an attempt to perform a mass balance. 364 3. Tape or overlays should not be used in studies where the TDS is used to calculate 365 residual drug. 366 4. TDS adhesion assessments should be conducted over the entire period of wear to 367 determine whether the TDS diffusional surface area remains in full contact with the 368 skin during the entire period of the study. 369 5. A control study should be performed to provide an estimate of drug load, rather than 370 simply using the expressed label claim. This study should include analysis of a 371 minimum of three unused products from the same lot of product used in the study. 372 6. Sample storage conditions before and after application of the TDS on the skin should 373 be validated. Photostability and thermal stability of the active ingredient(s) in the 374 TDS should also be considered when selecting the appropriate storage conditions. 375 7. Appropriately sensitive and valid analytical methods should be used to assay the 376 residual drug content for the purpose of calculating drug depletion and delivery. 377 When estimating the amount of residual drug in the TDS, a drug extraction method 378 with a target extraction efficiency close to 100 percent should be utilized to minimize 379 error. 380 381 f. In Vitro Permeation Testing 382 383 In vitro permeation testing (IVPT) with the use of excised human skin may be utilized to 384 characterize the rate and extent of transdermal or topical drug delivery, and the study protocols 385 and results should be described in the application. The following factors should be considered 386 during IVPT model development: 387 388 • Selection of the diffusion apparatus and the operating conditions like stirring rate or flow 389 rate, as well as temperature control to maintain the under-normal-conditions skin surface 390 temperature (32°C ±1°C) 391 392 • Source of the skin, skin storage conditions, choice of skin type (i.e., age range, sex , race, 393 and consistent anatomical region) and the skin preparation technique (e.g., full-thickness, 394 dermatomed, isolated epidermis) 395 396 The IVPT protocol should specify the nominal skin thickness and its range, details of the skin 397 barrier integrity test, and any occlusion of the product during the IVPT. Visual observations 398 alone are not sufficient to characterize the barrier integrity of the skin. Acceptable barrier 399 integrity tests may be based on tritiated water permeation, trans-epidermal water loss (TEWL), 400 or electrical impedance/conductance measured across the skin. The test parameters and 401 acceptance criteria used for the skin barrier integrity test should be justified based on relevant 402 literature references or other information.

12 Contains Nonbinding Recommendations Draft — Not for Implementation 403 404 The IVPT protocol should also include details about the receptor solution, system equilibration, 405 procedures for skin mounting and application of the TDS, as well as any measures to secure the 406 TDS on the skin surface to prevent lifting. We recommend that an antimicrobial agent be 407 included in the receptor solution (e.g., ~0.1 percent sodium azide or ~0.01 percent gentamicin 408 sulfate). 409 410 The IVPT study report should include dose duration, sampling duration, sampling time points, 411 concentration of samples, concentration of the antimicrobial component, and the empirical 412 stability (at relevant temperatures) and solubility of the active ingredient in the receptor solution. 413 The study report should also include the number of individuals whose skin was evaluated (i.e., 414 skin donors) and the number of replicate skin sections per donor per treatment group. 415 416 All treatment groups compared in an IVPT study should be dosed on the skin samples from the 417 same set of donors, with the same number of replicates per donor per treatment group. These 418 treatment groups should also use the skin samples from the same anatomical site from all donors, 419 unless varying these parameters is essential to the design of the study and the evaluation of the 420 TDS. The study report should include the equilibrated skin surface temperature prior to dose 421 application, and the ambient temperature and relative humidity in the laboratory, as well as the 422 extent of qualification of the sample analytical methods (e.g., HPLC). 423 424 g. Extractable and Leachable Testing 425 426 All TDS should be evaluated for potential compounds that could be transferred from the product 427 to the patient. This evaluation should include assessments of extractables and leachables, 428 consistent with USP <1663> and <1664>. 429 430 As defined in United States Pharmacopeia (USP)21 General Chapter <1663> Assessment of 431 Extractables Associated with Pharmaceutical Packaging/Delivery Systems, “extractables are 432 organic and inorganic chemical entities that are released from a pharmaceutical packaging/ 433 delivery system, packaging component, or packaging material of construction and into an 434 extraction solvent under laboratory conditions.” The extraction conditions should “accelerate or 435 exaggerate the normal conditions of storage and use for a packaged dosage form.” 436 437 As defined in USP General Chapter <1664> Assessment of Drug Product Leachables Associated 438 with Pharmaceutical Packaging/Delivery Systems, “leachables are foreign organic and inorganic 439 entities that are present in a packaged drug product because they have leached into the packaged 440 drug product from a packaging/delivery system, packaging component, or packaging material of 441 construction under normal conditions of storage and use or during accelerated drug product 442 stability studies.” 443 444 In the context of this guidance, extractable impurities are chemical entities that can be drawn out 445 of the backing membrane, release liner, pouching material, printed ink, internal membranes, and 446 components other than the drug substance and adhesive matrix by a solvent system. 447 Additionally, an extraction study can detect compounds introduced into the TDS from the

21 USP references in this guidance refer to USP 41–NF 36.

13 Contains Nonbinding Recommendations Draft — Not for Implementation 448 manufacturing process, which can impact the final impurity profile of the TDS product. In the 449 context of this guidance, leachables are chemical entities present in a packaged TDS because 450 they leached into the adhesive matrix (or where applicable, reservoir) under normal conditions of 451 storage or during accelerated stability studies. These compounds may transfer from the adhesive 452 matrix (or reservoir) to the patient during use. 453 454 Extractable studies are used to inform the leachable study design. The leachable data should be 455 correlated, if possible, with the extractables profile(s) determined under the various control 456 extraction study conditions. Both extractable and leachable studies should have adequate 457 sensitivity to detect compounds potentially released at a level associated with patient exposure 458 when a product is used at the maximum daily dose (e.g., 1.5 mcg/day for standard mutagenic 459 compounds in a chronic-use drug product22), unless otherwise justified. For some products, the 460 maximum daily dose may require applying more than one TDS. 461 462 Adhesive impurities such as residual monomers, initiator byproducts, and aldehydes are not 463 considered extractables or leachables because these impurities are present at peak concentrations 464 before product manufacture. Control of adhesive impurities is discussed elsewhere in this 465 guidance (see section IV. INFORMATION TO BE SUBMITTED IN AN APPLICATION, C. 466 Control of TDS Product). However, the leachable studies discussed below may be leveraged to 467 justify adhesive impurity limits or as part of the toxicological risk assessment for adhesive 468 impurities because a leachable study is performed on the proposed commercial product. 469 470 To aid in the extractable and leachable analyses described below, applicants should contact raw 471 material suppliers to identify potential extractables of toxicological concern, such as residual 472 monomers from backing materials. 473 474 i. Extractable Studies 475 476 Extractable studies should be conducted early in the pharmaceutical development process to 477 understand the potential leachables from components of the proposed commercial TDS. These 478 studies should be conducted on components such as backing membrane, release liner, rate 479 controlling or other internal membranes, ink and pouching. The testing components should be 480 extracted in a variety of solvents with a range of polarities under vigorous laboratory extraction 481 conditions to maximize the levels of extractables and identify as many potential leachables as 482 possible. One of the extraction solvents used in the extractable studies should include the solvent 483 of the proposed commercial adhesive(s) platform or the known residual solvents for the finished 484 TDS. The choices of solvents used should be justified. 485 486 ii. Leachable Studies 487 488 The conditions of the leachable studies should mimic as closely as possible the “worst-case” 489 clinical conditions of the skin (e.g., sweating during rigorous exercise). The solvent/solution 490 selection (such as salt concentrations), temperature, level of agitation, duration of exposure to the 491 solvent, etc., selected for the studies should be justified. The release liner should be removed

22 See FDA guidance for industry M7(R1) Assessment and Control of DNA Reactive (Mutagenic) Impurities in Pharmaceuticals To Limit Potential Carcinogenic Risk (March 2018).

14 Contains Nonbinding Recommendations Draft — Not for Implementation 492 from the system during the study to adequately expose the adhesive layer to the biologically 493 relevant solvent. Applicants should conduct a multi-timepoint leachable analysis (e.g., 0, 6, 12, 494 24 months) to provide a comprehensive leachable profile and identify any trends in leachables as 495 these data could impact the shelf life of the product. At the time of application submission, data 496 should be submitted from a leachable study performed on samples from multiple batches stored 497 at a minimum of 6 months under accelerated and long term conditions. We recommend 498 conducting leachable studies on the same three distinct laminates of TDS placed on stability 499 testing. 500 501 h. Assessing the Effects of Heat 502 503 Heat from external sources such as a heating blanket, and potentially from a rise in internal body 504 temperature due to strenuous exercise or fever, may affect the rate of drug release from the TDS 505 and the absorption of drug into and through the skin. We recommend that applicants study the 506 impact of an elevated TDS/skin surface temperature on the delivery profile of TDS relative to its 507 delivery profile at a normal TDS/skin surface temperature. 508 509 For a TDS product to be submitted in an NDA, we recommend that the heat effect studies be 510 conducted as part of a clinical study using the proposed commercial product. In designing the 511 heat effect studies, critical factors such as appropriate elevated test temperature(s), heat exposure 512 onset time(s), duration(s), and cycles (if any), as well as mechanisms of heat exposure (e.g., 513 heating lamp, heating pad, etc.) should be identified. 514 515 For a TDS product to be submitted in an ANDA, the applicant should evaluate whether the test 516 TDS, used under elevated temperature conditions, increases drug delivery compared to the 517 reference (R) TDS. The ANDA applicant should provide the results of an IVPT study comparing 518 the drug delivery characteristics for the test TDS and the R TDS at normal and elevated 519 temperatures using skin from multiple individuals (donors), with multiple replicate diffusion 520 cells evaluated per donor, per treatment (test versus R), and per temperature condition. An IVPT 521 study with a sufficient number of donors and replicates per donor per treatment per temperature 522 condition is recommended to obtain meaningful data. A study with fewer than four donors and 523 four replicates per donor per treatment per temperature may be difficult to interpret. 524 525 We recommend a parallel evaluation and comparison of the test and R TDS under the following 526 baseline and elevated temperature conditions: 527 528 1. BASELINE: Both the test and R products should be maintained at a TDS/skin surface 529 temperature of 32 ±1°C for the entire study duration. 530 531 2. ELEVATED TEMPERATURE: Both the test and R products should be maintained at 532 a TDS/skin surface temperature of 32 ±1°C until a specified time, approximately 533 when the peak flux is observed, and then maintained at a TDS/skin surface 534 temperature of 42 ±2°C for a period thereafter, which may be the remainder of the 535 study duration. 536

15 Contains Nonbinding Recommendations Draft — Not for Implementation 537 It should not be assumed that a set temperature for a circulating water bath will provide the target 538 temperature at the TDS/skin surface. The TDS/skin surface temperature should be directly 539 measured using an infrared thermometer or other temperature probe. The study duration for a 7- 540 day wear TDS need not encompass the entire labeled duration of wear. It may be adequate to 541 perform an IVPT study for a 48 or 72 hour duration, if that duration is sufficient to reach the 542 peak drug delivery rate under baseline conditions. Alternatively, an applicant may justify 543 evaluating other conditions or scenarios of exposure to elevated temperatures that represent the 544 worst-case scenario for a given TDS product or indicated patient population. 545 546 i. Microscopic Matrix Evaluation 547 548 Due to complexities of many TDS formulations, adhesive matrices often do not form true 549 solutions, rather they manifest as dispersions. If rearrangements of the dispersed-like system 550 occur over time within the matrix, they can possibly lead to lack of adhesion or changes in drug 551 delivery and release. As such, it is important to have a good understanding of the TDS 552 formulation, the way the drug substance and excipients are dispersed within the adhesive matrix, 553 and the tendency of the matrix to change over time from product release through its expiry 554 period. Therefore, it is informative to assess surface and cross-sectional changes in the TDS 555 matrix throughout the shelf life of the developmental batches using high-powered microscopy, 556 elemental mapping, or other appropriate tools. These tools may not be appropriate for every 557 TDS; applicants should provide a scientific justification for the tools used. These assessments 558 will help achieve comprehensive understanding of product and process, mitigate quality-related 559 risks, and assure that the TDS meets the requisite quality attributes through its expiry period. 560 561 4. Proposed Manufacturing Changes 562 563 Scale-up proposals and other process changes may be proposed in an original NDA or ANDA, 564 but the level of additional information needed to support these changes will generally be 565 commensurate with the risk of the change to adversely impact product quality. In general, 566 changes to TDS after the conduct of pivotal clinical studies should be avoided when possible 567 because of the sensitivity of TDS to small changes in formulation and manufacturing process. 568 569 Low-risk changes may be adequately supported with updated master batch records and batch 570 formulas. Examples include scale-up of solvent-based and aqueous mixtures within a factor of 10 571 using equipment of the same design and operating principles, or proposing a change to 572 converting and pouching equipment of the same design and operating principle. 573 574 Moderate-risk changes may warrant additional developmental studies and stability data on 575 commercial scale batches to demonstrate that they will not result in an adverse impact on the 576 quality of the product. Examples of such changes may include scale-up of hot-melt mixtures 577 within a factor of 10, scale-up of screw-based mixing processes, and changes to 578 coating/drying/laminating equipment of the same design and operating principle. 579 580 Changes that pose a high risk to quality may warrant additional in vivo studies. An example is 581 changing the manufacturing process to incorporate equipment of a different design and operating 582 principle.

16 Contains Nonbinding Recommendations Draft — Not for Implementation 583 584 B. Manufacture 585 586 As described in ICH M4Q, section 3.2.P.3 of the application should contain information about 587 where and how the TDS product will be manufactured. The batch formula and a description of 588 the manufacturing process and process controls should be provided. A detailed schematic 589 diagram of the proposed production process, including descriptions of the equipment, operating 590 conditions, and process controls, should also be provided.23 591 592 During process development, the applicant should identify process variables that have a potential 593 to impact TDS product CQAs. These process development studies inform commercial process 594 qualification and continued process verification later in the product life cycle. 595 596 Typical TDS manufacturing steps/unit operations are listed below (a non-exhaustive list). For 597 processes that incorporate these steps, the applicant should describe how each operation and 598 associated controls were developed, addressing the considerations below, specifically, the CQAs 599 that may be impacted by the operation, and the relevant process parameters and material 600 attributes that may impact the output of each operation: 601 602 o Mixing: Mixing operations produce bulk mixtures for the coating step. Mixing can 603 impact CQAs such as assay, stability of drug substance and/or excipients, content 604 uniformity, microscopic appearance, and physical properties of the adhesive. The 605 control strategy should address the impact of equipment design, order of material 606 addition, and process parameters (such as mixing speeds, mixing times, temperatures, 607 redispersion or recirculation conditions, and deaeration conditions) on CQAs, and 608 should be justified, as necessary, based on development studies. CMAs that can 609 impact mixing include drug substance particle size, polymorphic form, raw material 610 rheological attributes, and percent solids for materials supplied in solvent-based 611 mixtures. 612 613 o Coating, drying, and lamination: Coating is the application of a mixture to a substrate. 614 Depending on the equipment used, coating can impact CQAs such as content 615 uniformity and microscopic appearance. Though CPPs are equipment dependent, 616 firms should demonstrate that the control strategy (e.g., process parameters to be 617 controlled) is adequate to ensure content uniformity and microscopic appearance for 618 the full duration of the coating operation. CMAs that can impact coating include the 619 rheology of the bulk mixture and within-roll uniformity of the substrate to be coated. 620 621 Drying involves the removal of solvent from the mixture following the coating 622 process. This process step can impact CQAs such as assay, permeation enhancer 623 content, antioxidant content, water content (for hydrogels), content uniformity, 624 microscopic appearance, drug release, product stability, residual solvents, residual 625 adhesive impurities, and physical properties of the adhesive matrix. Therefore, CPPs 626 for drying that may need to be considered during process development include line

23 See 21 CFR part 314.50(d)(1)(ii)(c).

17 Contains Nonbinding Recommendations Draft — Not for Implementation 627 speed, the pump or screw speed, zone temperatures, air flow rates, temperature of the 628 drying air, and humidity of the drying air. Process development should also consider 629 the CMAs that can impact drying such as solvent and adhesive impurity content in the 630 bulk mixture. Applicants should also provide data to justify any drug substance 631 overage or excipient excess that may be needed to compensate for any evaporation 632 during drying. 633 634 Lamination involves the combining of multiple layers of a given transdermal system 635 design into a single common laminate. Applicants should provide development data 636 for corona treatments if such a process is used to bond the adhesive to a backing film 637 or rate-controlling membrane. 638 639 o Slitting and Printing: The bulk product is typically slit longitudinally into narrower 640 rolls of laminate for further processing. Slitting and printing are typically low risk 641 steps; however, if certain aspects of the printing processes, e.g., excessive penetration 642 depth or heat input, can adversely affect product quality, then printing processes 643 should be characterized and controlled. 644 645 o Converting and pouching: Converting and pouching typically involve cutting a 646 continuous laminate into individual units and sealing the unit in a heat-sealed pouch. 647 CQAs affected by these processes include usability of the product (e.g., the ability to 648 remove a release liner) and pouch integrity. Common CPPs for these steps include 649 heat sealing temperatures and dwell times. 650 651 o Curing: Some TDS have processing steps to complete a curing reaction after drying 652 or pouching. Curing time and curing conditions are common CPPs for this step. 653 Curing should be completed before batch release testing if curing could impact test 654 results. 655 656 o Hold times: Hold times must be defined and justified for in-process materials held 657 between unit operations (21 CFR part 211.111). Applicants should use a risk-based 658 approach to determine which CQAs to monitor during hold time studies. 659 660 o Other considerations: Tubing and other product-contact equipment must be qualified 661 as non-reactive, non-additive, and non-absorptive (21 CFR part 211.65(a)). The 662 selection of the tubing and certain product-contacting equipment should be risk- 663 based, i.e., dependent on the duration of contact, process temperature, solvent system, 664 material considerations, clearance of leachables during manufacturing, and clinical 665 use considerations. 666 667 In-process controls (IPCs) for TDS are an integral part of the control strategy. The description of 668 the proposed IPCs should address the following: 669 670 • At the mixing stage, IPCs can provide assurance of assay, viscosity, uniformity, and 671 pH for aqueous mixtures. If multiple samples are taken from a dispersed mixture,

18 Contains Nonbinding Recommendations Draft — Not for Implementation 672 applicants should specify the mean, range for individual samples, and percent relative 673 standard deviation. 674 675 • IPCs for coating, drying, and lamination can provide assurance of uniformity across 676 the laminate and throughout the run. For example, measurements for film appearance, 677 coat weight, and/or a test for residual solvents may be applicable IPCs for coating and 678 drying. Film appearance measurements that allow detection and rejection of defects 679 affecting continuity of an adhesive laminate (e.g., streaks) should be described in the 680 application. Additionally, for films that are dispersions at the microscopic scale (e.g., 681 acrylic adhesive dispersed in silicone, povidone dispersed in silicone, or solid drug 682 substance dispersed in adhesive), applicants should describe the IPCs established to 683 monitor uniformity throughout a coating run in the application. Samples for testing 684 coat weight and uniformity should be representative of the full length and width of a 685 laminate. Alternatively, these attributes can be monitored continuously (e.g., by the 686 use of in-line coating measurement tools). In cases where the upstream controls can 687 be used to confirm certain finished TDS specifications, such as residual solvents and 688 residual adhesive impurities, IPC testing can be used in lieu of release testing for 689 these attributes.24 690 691 • For converting and pouching, IPCs can provide assurance of pouch integrity, product 692 placement within the pouch, and product appearance (e.g., adequacy of the printed 693 label, die-cuts, and kiss-cuts). An automated system can perform in-process checks 694 for product appearance in lieu of human operators if the automated system is 695 demonstrated to be suitable for the intended task(s). 696 697 C. Control of TDS Product 698 699 Section 3.2.P.5 of the application should contain the following information on control of the 700 TDS product: 701 702 • Specification 703 • Analytical procedures 704 • Validation of analytical procedures 705 • Characterization of impurities 706 • Batch analyses 707 • Justification for the proposed specification 708 709 Typical CQAs included in TDS specification: 710 711 • Description 712 • Identification 713 • Assay

24 See Questions and Answers on Current Good Manufacturing Practices, Good Guidance Practices, Level 2 Guidance - Records and Reports at the following site: http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm124787.htm.

19 Contains Nonbinding Recommendations Draft — Not for Implementation 714 • Impurities and degradation products 715 • Uniformity of dosage units 716 • Permeation enhancer content, when applicable 717 • Adhesion 718 • Release liner peel 719 • Tack 720 • Shear 721 • Cold flow 722 • In vitro drug release 723 • Drug substance crystal presence 724 • Pouch integrity 725 • Microbial limits, when applicable25 726 • Moisture content, when applicable 727 • Residual solvents 728 729 The proposed analytical procedures should be documented in sufficient detail that they can be 730 reviewed and reproduced in FDA laboratories. In some cases, if upstream controls can be used to 731 confirm that a batch of product meets a CQA listed on the specification, that attribute may not 732 need to be tested at release for every batch, but should be indicated as such on the 733 specification.26 Applicants proposing a control strategy using such an approach should provide 734 justification. 735 736 Some of the methods and criteria associated with CQAs typical for TDS are described below. 737 738 a. Adhesive Impurities 739 740 Adhesives may contain residual monomers, initiator byproducts, aldehydes, etc. The safety of 741 these compounds should be assessed, as some of these compounds are classified as neurotoxic 742 (e.g., tetramethylsuccinonitrile) or mutagenic (e.g., crotonoaldehyde). Manufacturers are 743 encouraged to contact the raw material suppliers to discuss the selected adhesive raw material 744 and all potential impurities, as some impurities may not be reported on the certificates of analysis 745 provided by the supplier. Applicants should discuss the potential impurities arising from the raw 746 material in the application. A control strategy for any impurity of toxicological relevance should 747 be established and justified. The control strategy may include testing at the raw material stage, 748 demonstrating that the manufacturing process is capable of consistently removing the impurities 749 of concern, testing of the final laminate, or a combination of the above. 750 751 To support a proposed control strategy based on the capability of the manufacturing process to 752 consistently remove any impurities of concern, applicants should provide data to demonstrate a 753 reduction in the level of the impurity in the final laminate (or finished product) compared to the

25 When applicable, we recommend manufacturers assess the risk of microbiological contamination to their TDS in order to establish the appropriate microbiological tests, specification, and manufacturing operations for their product. Based on this risk assessment, manufacturers should leverage existing approaches (ICH guidelines, USP standards, FDA guidance, etc.) to determine the testing necessary for their product. 26 See FDA guidance for industry Q8(R2) Pharmaceutical Development.

20 Contains Nonbinding Recommendations Draft — Not for Implementation 754 level in the same batch of raw material.These data are necessary to quantitatively demonstrate 755 effectiveness of the manufacturing process in removing the impurity and to establish controls for 756 adhesive impurities based on levels in the raw material rather than on the final product. 757 758 Applicants may consider leveraging the leachable study discussed in the pharmaceutical 759 development section of this guidance by testing adhesive impurities in the leachate. The 760 leachable information can be used to provide toxicological justification for impurity limits or the 761 information can be included as part of the toxicological risk assessment. 762 763 b. Uniformity of Dosage Units 764 765 TDS specifications should include a test and acceptance criterion for content uniformity for the 766 dosage units. If the finished TDS is designed to be cut by the user, uniformity should also be 767 demonstrated among pieces cut from a single unit. 768 769 c. Permeation Enhancer Content 770 771 Products that utilize permeation enhancers to establish or maintain drug delivery should include 772 a test and acceptance criterion for permeation enhancers at release and throughout stability. An 773 acceptance criterion that is wider than the typical range for a particular permeation enhancer may 774 require in vivo justification in the absence of an in vitro in vivo correlation. 775 776 d. Adhesion Testing (Peel Adhesion, Release Liner Peel, Tack, and Shear Tests) 777 778 Using currently available methods, in vitro adhesion testing does not correlate to in vivo 779 adhesion, but in vitro adhesion testing can be useful for quality control (QC) purposes. In vitro 780 adhesion testing should include peel adhesion, release liner removal, tack, and shear (dynamic or 781 static).27 There are multiple methods and different experimental parameters for each of the tests. 782 783 The peel adhesion test measures the force required to remove (peel away) a TDS that has been 784 applied to a standard test panel (e.g., polished stainless steel). The measurement of peel adhesion 785 is influenced by the test parameters such as dwell time, substrate (e.g., stainless steel, high 786 density polyethylene (HDPE)), peel angle, and peel speed. 787 788 A release liner peel test measures the force required to separate a TDS from its release liner. The 789 measurement of release liner peel is influenced by experimental parameters such as peel angle 790 and peel speed. 791 792 The probe tack test measures the force required to separate the test probe from the adhesive of 793 the TDS. Tack measurement is influenced by the test parameters such as the contact area, the 794 contact pressure, the time of contact (or dwell time), and rate of separation. 795 796 There are two categories of shear testing, namely dynamic and static. In the dynamic test, the 797 TDS is pulled from a standard test panel (e.g., polished stainless steel). Dwell time, speed, type 798 of test panel, mode of failure, and sample size are the typical test parameters reported for the

27 See USP 41–NF 35 General Chapter <3> Topical and Transdermal Drug Products-Product Quality Tests.

21 Contains Nonbinding Recommendations Draft — Not for Implementation 799 dynamic shear test. In the static shear test, the TDS sample is applied to a test panel that is at an 800 angle 2° from the vertical, and the sample is subjected to a shearing force by a means of a given 801 weight (e.g., 1000 g) suspended from the TDS; the time required to detach a standard area of the 802 TDS from a stainless steel test panel under a standard load is measured. Dwell time, weight used, 803 type of test panel, mode of failure, and sample size are the typical test parameters reported for 804 the static shear test. The time taken for the TDS sample to detach from the test panel is also 805 reported. 806 807 e. Cold Flow 808 809 Cold flow is the creeping or oozing of the adhesive matrix beyond the perimeter of the backing 810 membrane or through the release liner slit. Cold flow may be present on the TDS, release liner, 811 pouch, or disposable films (sometimes termed slip sheets or protective films, such as a film over 812 the backing and a film over the release liner). Though a quantitative method of assessing cold 813 flow can provide a meaningful measurement, it may not describe the difficulty in removing the 814 TDS from the pouch or the protective films from the TDS. The most accurate cold flow 815 assessment for TDS will likely come from a combination of product-specific quantitative and 816 qualitative methods. 817 818 The test methods should be discriminating and scientifically justified. Manufacturers should 819 propose product-specific acceptance criteria with justification supported by product development 820 research. 821 822 f. In vitro Drug Release 823 824 USP General Chapter <724> describes the apparatuses to use for in vitro release testing and the 825 acceptance criteria for each apparatus; however, method development and validation is not 826 addressed. General recommendations for in vitro release testing of TDS are described below 827 along with considerations for method design and validation. 828 829 In vitro drug release testing of TDS products is typically performed using specific, qualified 830 apparatus such as: Paddle over Disk (Apparatus 5), Cylinder (Apparatus 6), or Reciprocating 831 Holder (Apparatus 7). 832 833 The NDA or ANDA submission for the TDS product should include a method development and 834 validation report with complete information/data supporting the proposed drug release method 835 and acceptance criteria. 836 837 Sufficient detail and data should be included in the method development and validation report so 838 the adequacy of the method for batch release and stability testing can be properly assessed. 839 Examples of parameters to evaluate during method development include selection of USP 840 apparatus/other equipment, drug release medium, rotation or agitation speed, temperature, pH, 841 sink conditions, use of a surfactant, and other technical aspects of the test. An in vitro drug 842 release method should be simple, reliable, reproducible, discriminating, and robust. Applicants 843 should strive to develop a method that releases as much drug as possible. 844

22 Contains Nonbinding Recommendations Draft — Not for Implementation 845 The validation section of the report should include complete information/data regarding: i) the 846 discriminating ability of the selected method, ii) the validation of the drug release methodology, 847 and iii) the validation/verification of the analytical method selected to assay the drug release 848 samples. The selected method should be able to differentiate the release profiles of TDS that are 849 intentionally manufactured with meaningful variations in critical process parameters and 850 formulation components. Validation data should demonstrate the range and sensitivity of the 851 method for proportional drug release across different strengths of the TDS. In addition, 852 validation data should demonstrate reproducibility of the method for drug release across different 853 runs of the same batch and its robustness, i.e., its capacity to remain unaffected by changes in 854 receptor medium temperature, paddle rate, and other method parameters. 855 856 The acceptance criteria for the in vitro drug release test should be based on the proposed TDS 857 product batch release data, including data from bio-batches (e.g., BE, PK, Clinical), 858 registration/exhibit batches, and commercial batches (if available). To set the acceptance criteria 859 for the in vitro drug release test, a complete drug release profile should be established by 860 collecting data until there is no increase in drug release over three consecutive time points 861 (sampling every 2 hours). The drug release profile of TDS products typically encompasses 862 initial, middle, and terminal phases; thus, for setting the acceptance criteria, there should be at 863 least one sampling time point covering each phase. The drug release data should be reported as 864 the cumulative percent of drug being released with time. The acceptance criteria range for each 865 specific timepoint should be based on the mean percentage value of drug released ± 10 percent 866 using the drug release data generated at these times. The percentage should be determined based 867 on the TDS product’s label claim. If less than 100 percent drug is released, but no drug increase 868 is observed over three consecutive sampling timepoints (i.e., incomplete drug release), the 869 amount of drug reached at the plateau should be considered 100 percent for the purposes of 870 estimating the percent of drug release over time. 871 872 Wider acceptance criteria range for the drug release test may be acceptable if they are supported 873 by an approved in-vitro in-vivo correlation model. 874 875 g. Crystal Presence 876 877 The presence of crystals or crystallization of the drug in the TDS over time can negatively 878 impact the product performance. Therefore, it is important to establish a test and acceptance 879 criteria to confirm the absence of crystals to be used at release and on stability. Microscopic and 880 photometric methods are preferred rather than a simple visual count. It is recognized that some 881 products are designed to be suspensions, however, this design does not preclude the need for a 882 crystal specification. Suspension products should still include tests and acceptance criterion to 883 ensure against crystal propagation, which may impact drug delivery or adhesion properties of the 884 product. 885 886 h. Pouch Integrity 887 888 The pouch for a TDS is critical to the stability and integrity of the product. Pouch integrity 889 testing should be conducted as part of finished product release unless justification is provided for 890 an alternative approach that assures the finished product specification is met.

23 Contains Nonbinding Recommendations Draft — Not for Implementation 891 892 D. Additional Stability Studies 893 894 In addition to the standard battery of formal stability and photostability studies for drug 895 substance and drug products discussed in ICH Q1A and ICH Q1B,28 TDS applicants and 896 manufacturers should conduct stability studies under challenge conditions that include 897 temperature excursions, freeze/thaw, and/or crystal seeding. These additional studies are 898 intended to address certain product quality issues such as crystal formation and growth. 899 Moreover, in-use photostability testing may be appropriate to conduct for certain TDS 900 formulations, depending on backing membrane opacity, duration of wear, and its expected 901 exposure to light when in use. 902 903 V. SPECIAL TOPICS 904 905 A. Product Adhesion Considerations 906 907 In vivo adhesion studies provide the greatest prediction of adhesion, a CQA, for a proposed 908 commercial product. Applicants should demonstrate that reasonable efforts were made to 909 optimize adhesive characteristics of the TDS. This optimization should balance properties such 910 as adhesiveness, cohesiveness, and stability to ensure a consistent and uniform adhesion of its 911 entire surface area to the skin for the entire duration of wear. Applicants should develop a 912 comprehensive strategy for assessing the adhesive attributes of the TDS. In vivo adhesion studies 913 are necessary to demonstrate adequate adhesion of the TDS. Therefore, when possible, such as in 914 efficacy studies for an NDA, subject diaries describing the actual in-use product adhesion 915 performance should be used. This information bolsters adhesion data collected from the studies 916 described below and in other guidances.29 917 918 Characterization of the adhesive properties of a TDS should demonstrate that the labelled uses 919 are substantiated. For example, if the TDS is intended to be worn during bathing and showering, 920 applicants should demonstrate that the TDS will continue to adhere during and after such 921 incidental exposure to water. Product reinforcement, such as taping the edges or use of overlays, 922 or occluding the product from water during bathing should not be permitted during the in vivo 923 adhesion evaluation. 924 925 We recommend that when assessing the adhesion of a TDS, applicants use a 5-point numerical 926 scale in which each score corresponds to a specified range of adhered surface area of the TDS, as 927 follows: 928 929 0 = ≥ 90% adhered (essentially no lift off the skin) 930 1 = ≥ 75% to < 90% adhered (some edges only lifting off the skin) 931 2 = ≥ 50% to < 75% adhered (less than half of the TDS lifting off the skin)

28 See FDA guidances for industry Q1A(R2) Stability Testing of New Drug Substances and Products (November 2003), and Q1B Photostability Testing of New Drug Substances and Products (November 1996). 29 See FDA draft guidance for industry Assessing Adhesion with Transdermal Delivery Systems and Topical Systems for ANDAs (October 2018). When final, this guidance will represent the FDA’s current thinking on this topic.

24 Contains Nonbinding Recommendations Draft — Not for Implementation 932 3 = > 0% to < 50% adhered (not detached, but more than half of the TDS lifting off the 933 skin without falling off) 934 4 = 0% adhered (TDS detached; completely off) 935 936 Additionally, the following information should be collected: 937 938 • At each time point when adhesion is assessed on the above described 5-point scale, 939 the scorer should also record their actual percent adherence estimate (e.g., if the 940 observer scores the product as a two on the five point scale and estimates that the 941 product appears to be 60 percent adhered, a score of two and a 60 percent should be 942 recorded for that time point). 943 944 • Photographic evidence showing the extent of TDS adherence to the skin at each time 945 point should be provided. 946 947 B. Product Storage and Disposal – Labeling Considerations 948 949 TDS storage conditions should be supported by stability data and stated in the label. Generally, 950 we recommend controlled room temperature for the storage of TDS. Excursions, if permitted, 951 should be indicated on the label. The label should also state that TDS should not be stored 952 outside of the pouch if that is necessary to preserve the safety, efficacy, and quality of the TDS. 953 954 Transdermal and topical delivery systems often contain post-use residual drug in the delivery 955 system. Considering the therapeutic nature of the drug compound and potential adverse events 956 resulting from unintended exposure, the instruction for product disposal should be clearly 957 outlined in the labeling. It is important that the disposal process prevents exposure of the residual 958 drug to the environment and/or other people. Depending on the nature of the product, special 959 instructions may be required to prevent exposure to children and caregivers, which could result 960 in significant safety-related consequences.